This project is designed to study the pathophysiology of acute cerebral hypoxia, as well as the aftereffects of exposure to hypoxia. The intent is to discover the effect of oxygen insufficiency itself, as distinct from effects mediated by changes of cerebral circulation. Slices of cerebral tissue will be maintained in vitro and exposed to hypoxia of varying degree and duration. The conditions will be defined in which reversible and irreversible changes of synaptic function occur. Tissue pH and other ion concentrations will be measured with ion selective microelectrodes. Tissue pO2 will be determined by polarography. Membrane properties of reversibly and irreversibly impaired neurons will be determined by intracellular methods and by voltage clamping. The roles of ions, of pH, and of post-hypoxic excess oxidant in influencing recovery will be studied. The possible protective effect of nutrients, metabolites and drugs against hypoxic damage will be determined. Findings in vitro will be compared with observations on intact brains in experiments performed in cooperation with Dr. Sylvia. Hypoxic changes of interstitial ions and of electrophysiological function will be related to biochemical changes. The chronic aftereffects of exposure to hypoxia will also be studied. Altered neuronal function caused by severe but transient oxygen deprivation will be determined as well as possible adaptation to prolonged, moderate lack of oxygen.